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This is a repository copy of Targeting interleukin-6 in rheumatoid arthritis.
White Rose Research Online URL for this paper:http://eprints.whiterose.ac.uk/85075/
Version: Accepted Version
Article:
Md Yusof, MY and Emery, P (2013) Targeting interleukin-6 in rheumatoid arthritis. Drugs, 73 (4). 341 - 356. ISSN 0012-6667
https://doi.org/10.1007/s40265-013-0018-2
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TARGETING IL-6 IN RHEUMATOID ARTHRITIS
Authors: Md Yuzaiful Md Yusof1, Paul Emery1*
.
1. Division of Rheumatic and Musculoskeletal Disease, Leeds Institute of
Molecular Medicine, University of Leeds and NIHR Leeds Musculoskeletal
Biomedical Research Unit, Leeds Teaching Hospitals, Leeds, UK.
* Corresponding author. Tel.: +44 113 3924884; Fax: +44 113 3924991
E-mail address: [email protected] (Paul Emery)
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TABLE OF CONTENTS:
Abstract……………………………………………………………………………………….4
1. Introduction…………………………………………………………………………..6
2. The role of IL-6 in the Pathogenesis of Rheumatoid Arthritis…………………..7
3. Tocilizumab and other IL-6 agents currently under development……………...9
4. Clinical Efficacy…………………………………………………………………….12
4.1 Tocilizumab Monotherapy…………………………………………………….13
4.2 Tocilizumab with Combination Therapy (Methotrexate/Other DMARDs)..17
4.3 Composite index without using acute phase reactants as measurement of
clinical efficacy……………………………………………………………………..21
4.4 Effect on Radiographic Progression………………………………………...22
4.5 Other Clinical Efficacy…………………………………………………………24
5. Safety Profile……………………………………………………………………….25
5.1 Infections……………………………………………………………………….25
5.2 Laboratory Abnormalities……………………………………………………..27
5.3 Malignancy……………………………………………………………………..28
5.4 Other Safety Profile……………………………………………………………28
6. Expert Opinion……………………………………………………………………..29
7. Conclusion………………………………………………………………………….31
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Abstract: 299 words
Pages: 46
Text (excluding abstract): 7244 words
Paragraphs: 75
Lines: 634
Characters (no spaces) 40 138
References: 84
Tables: 4
Keywords: Biological therapy; Interleukin-6; Tocilizumab; Rheumatoid Arthritis
4
ABSTRACT:
Interleukin-6 (IL-6) is a potent pro-inflammatory agent which plays a crucial
role in the pathogenesis of systemic inflammatory disease. Targeting this pathway in
rheumatoid arthritis (RA) seems an attractive option as IL-6 is important for both joint
destruction and systemic manifestations. Currently, tocilizumab which binds the IL-6
receptor is licensed for treatment in active, moderate to severe disease in RA and
systemic juvenile idiopathic arthritis (JIA). Several other promising IL-6 blocking
agents as well as a subcutaneous form of tocilizumab are currently undergoing
Phase III clinical trials. The aim of this article is to provide an up-to-date analysis of
clinical efficacy and tolerability data concerning the use of IL-6 inhibitors. Data from
clinical trials demonstrated that clinical efficacy for tocilizumab, which included
improvement in physical function and halting radiographic progression, were
comparable to other biologics licensed for use in RA. Patients who should gain most
are RA patients with systemic features such as high inflammatory markers and
anaemia. Perhaps, the strongest selling point lies in its effectiveness as a
monotherapy. This is particularly useful in those who are not tolerating combination
treatment with methotrexate. Tocilizumab is one of few biologics that has been
shown to be superior to methotrexate in head-to-head studies. The safety profile of
tocilizumab also is comparable to other currently available biologics. There is a small
but significant increase in adverse events including infections in patients treated with
tocilizumab compared to the placebo, particularly in patients who are elderly and
those with multiple comorbidities. Elevated lipid profiles are frequent but have not
been associated with major cardiovascular events. IL-6 blockade is a major
advancement in the treatment of RA as it targets a unique molecule. Over the next
5
few years, evidence will be available on the long-term cardiovascular safety and
efficacy of subcutaneous IL-6 blocking agents.
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1. Introduction:
Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease
characterised by symmetrical persistent synovitis affecting multiple predominantly
small joints. The disease also leads to fatigue, pain and other extra-articular
manifestations. It is a common disease with a prevalence of 1% worldwide [1]. If left
untreated, it will lead to significant joint destruction, reduced mobility and increases
the health care burden.
Since the introduction of early intervention concept in the early 1990s
[2], the management of our rheumatoid patients has shifted to a new paradigm.
Rheumatologists have become more proactive in identifying patients presenting with
early inflammatory arthritis symptoms and now treat them aggressively with the aim
of rendering the disease into remission at the earliest opportunity. Thus fewer RA
patients are seen with significant deformity these days.
Our understanding of the pathophysiology of RA has also improved
with an understanding of the various pathways of the cytokines that drive the
inflammatory cascades. These include the role of tumour necrosis factor,
interleukins-1 and 6, as well as the role of B and T-cells. As a result, we have various
options in treating our patients from the use of conventional synthetic Disease
Modifying Anti-Rheumatic Drugs (DMARDS) to the different biologics, which include
TNF-inhibitors such as infliximab, etanercept, adalimumab, golimumab and
certolizumab, rituximab (monoclonal anti-CD-20 providing B-cell depletion), anankira
(Interleukin-1 inhibitor) and abatacept (T-cell co-stimulatory inhibitor).
Despite the wealth of the different biologics, combination treatment
using DMARDs and biologics often raises safety issues. More importantly, there is a
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lack head-to-head success in regards to superiority of the biologics given as
monotherapy against methotrexate [3-5]. Even when a TNF-inhibitor is given in
combination with DMARDs, the rate of inadequate response has been quoted about
20-40% in various populations studied [6], prompting the clinician to switch to
different form of biologics. One novel treatment that shows promising results is
targeting Interleukin-6 (IL-6) which plays a pivotal role in the inflammatory cascade
and also halts radiographic structural progression. The aim of this article is to provide
a detailed critical analysis of clinical efficacy and tolerability data concerning the use
of IL-6 inhibitors. We will conclude with our expert opinion on the place of IL-6
inhibitors in the treatment of RA.
To achieve these objectives, a literature review of the published literature in
English language concerning the clinical efficacy and safety of IL-6 inhibitors in RA
was first undertaken using PubMed, Embase and Cochrane Library databases up to
November 2012. The keywords searched include ‘biologics,’ ‘interleukin-6,’
‘tocilizumab’ and ‘rheumatoid arthritis.’ Abstracts presented from 2008 to 2012 at the
American College of Rheumatology (ACR) and European League against
Rheumatism (EULAR) conferences were searched. Lastly, clinical trials that were
registered in the national registries were also sought.
2. The role of Interleukin-6 in the pathogenesis of Rheumatoid Arthritis
IL-6 is a pleiotropic cytokine, a 26-kDa glycopeptide encoded on
chromosome 7. It is produced by various cell types such as T cells, B cells,
monocytes, fibroblasts, osteoblasts, keratinocytes, endothelial cells, mesangial cells
and some tumour cells [7]. IL-6 can activate cells through 2 signalling pathways; the
8
first is the membrane-bound (mIL-6R) via activation of glycoprotein 130 and the
second is via proteolytic cleavage of the mIL-6R that leads to the generation of a
soluble receptor for IL-6 (sIL-6R) [8, 9]. The binding of IL-6 to sIL-6R enables the
stimulation of cells that lack endogenous soluble receptors (sIL-6R), thus widening
the number of cell types responsive to this cytokine [10, 11].
In relation to the pathogenesis of rheumatoid arthritis, IL-6 plays a role
in adaptive immunity. IL-6 stimulates B cells to differentiate into plasma cells which
produce immunoglobulin [12]. It also influences T-cell development by stimulating
the proliferation and differentiation of T lymphocytes into TH-17 cells which produce
IL-17. In vitro studies in mice have shown that the co-stimulation of IL-6 and TGF-く
is essential for the differentiation of Th17 cells from naive CD4+ T cells [13, 14].
Excess production of IL-6 has been found in the synovial fluid and
blood of RA patients and correlates with the disease activity and joint destruction [15,
16]. IL-6 promotes synovitis by inducing neovascularisation via vascular endothelial
growth factor (VEGF)-stimulated pannus proliferation, resulting in infiltration of
inflammatory cells and synovial hyperplasia [17]. In terms of joint erosion, IL-6
causes bone resorption by inducing osteoclast formation via the induction of RANKL
in synovial cells [18, 19], and cartilage degeneration by producing matrix
metalloproteinases (MMPs) in synovial cells and chondrocytes [20, 21].
In addition, this cytokine is responsible for mediating many of the
systemic manifestations of RA. It induces the acute-phase response particularly the
development of C-reactive protein (CRP), fatigue via the hypothalamic-pituitary-
adrenal (HPA) axis [22] and osteoporosis from its effect on osteoclasts. IL-6 also
affects a change in lipid concentrations in blood. Furthermore it induces the
9
production of hepcidin which is responsible for anaemia of chronic inflammation [23].
Thus IL-6 is a pleiotropic cytokine and a suitable target in the treatment of RA.
3. Tocilizumab and other IL-6 agents currently under development
Tocilizumab, a humanised anti-IL-6R antibody prevents IL-6 from
binding to both mIL-6R and sIL- 6R, thereby blocking the pro-inflammatory effects of
IL-6. Its molecular weight is ~ 150 Kd [24] and it binds to sIL-6R in a dose-dependent
manner and saturates the receptor at ~ 0.1µg/ml. It also competitively inhibits IL-6
binding to sIL-6R, with complete inhibition seen at ~ 4µg/ml [10].
Tocilizumab was initially developed by a collaborative effort between
the Osaka University and the Chugai Pharmaceutical Company (Ltd) Japan, a
subsidiary of Hoffman-LaRoche [25]. In Europe and the rest of the world it is given
intravenously at a dose of 8 mg/kg every 4 weeks. The subcutaneous form (162mg
weekly) is now entering the Phase III trial and the preliminary data showed
comparable efficacy and safety profiles to the established intravenous form [26]. In
the United States, the recommended starting dose for RA is 4 mg/kg, followed by an
increase to 8 mg/kg based on the clinical response. Starting at the lower dose may
not be ideal because of its insufficient efficacy in delaying remission, a higher risk of
anaphylactic reactions and increased risk of immunogenicity [27].
Currently, the use of tocilizumab is licenced for the treatment of RA and
systemic juvenile idiopathic arthritis (JIA). A recent Consensus indicated that
tocilizumab may be used in adult patients with active RA, normally with at least
moderate disease activity according to a validated composite measure, who have
10
had an inadequate response to, or intolerance of at least one synthetic DMARD
and/or a TNF-inhibitor [28]. In 2012, both the National Institute for Health and Clinical
Excellence (NICE) of the United Kingdom and the Food and Drug Administration
(FDA) agency of the United States have expanded the approved indication of
tocilizumab to be used as a “first-line biological agent” in RA patients who have had
an inadequate response to one or more synthetic DMARDs.
In Japan, it is also licensed for use in the treatment of Castleman’s
disease [29]. There are also case reports in regards to the use of tocilizumab in other
auto-immune conditions such as giant cell arteritis [30, 31], adult onset Still’s disease
[32] , systemic lupus erythematosus [33], ANCA-associated vasculitis [34], Behcet’s
disease [35, 36], systemic sclerosis [37] and polymyositis [38]. These reports
showed that tocilizumab was the salvage therapy used after disease resistance to
various former drugs. More open-labelled or randomised controlled trials are needed
to explore these in the future.
There are 4 other IL-6 agents that are currently under development, 3
of which are now entering the Phase III studies as summarized in Table 1. All but
one of these agents are administered as subcutaneous forms. Sarilumab is the first
fully human monoclonal antibody directed against IL-6Rg. The MOBILITY study, a
Phase II double-blind, multi-national trial recruited 306 adults with active, moderate-
to-severe RA who did not respond adequately to methotrexate (MTX-IR) [39].
Patients were randomised into 6 groups: sarilumab 100 mg 2-weekly, 150 mg 2-
weekly, 100 mg weekly, 200 mg 2-weekly, 150 mg 2-weekly or placebo (all in
combination with methotrexate). The results showed that the primary outcome,
American College of Rheumatology (ACR20 response) was met at 12 weeks and
was significant against the placebo (p=0.02) in the 150 mg every 2-weekly sarilumab
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arm, 72.0% and 46.2% respectively. The types and incidence of adverse events
were comparable to other IL-6 inhibitors.
BMS945429, a humanised monoclonal antibody that potently binds IL-
6 completed a phase II double blind randomised placebo-controlled trial [40]. 127
patients who were MTX-IR were randomised to 1:1:1:1 to BMS945429 (80, 160 or
320 mg; administered intravenously) or placebo plus methotrexate. At week 12, the
primary end point in the form of ACR20 response was achieved in 81% (80 mg; p <
0.0001 vs placebo), 71% (160 mg; p = 0.0005 vs placebo), 82% (320 mg; p < 0.0001
vs placebo) and 27% (placebo), respectively. Disease activity score in 28 joints
remission criteria (DAS-28 < 2.6) was also achieved at week 16 in 14% (80 mg),
28% (160 mg) and 44% (320 mg) of the BMS945429 groups. The other secondary
end point, clinical improvements in health-related quality of life (HRQoL), was also
statistically significant in the treatment groups.
Sirukumab is a humanised monoclonal antibody against the soluble IL-
6 receptor. It is administered subcutaneously. In the second part of the proof of
concept Phase II randomised controlled study, the investigators recruited 151 RA
patients who were MTX-IR. The patients were randomised equally to 5 treatment
arms; (i) placebo from week 0-10 followed by sirukumab 100mg every 2-weekly from
week 12–24, (ii) sirukumab 100mg every 2-weekly from week 0–24, (iii) sirukumab
100mg every 4-weekly from week 0–24, (iv) sirukumab 50mg every 4-weekly from
week 0–24 and (v) sirukumab 25mg every 4-weekly from week 0–24 [41]. At week
12, all of the sirukumab arms (in combination) significantly improved ACR50
response (overall p=0.010) and significantly reduced the DAS-28 scores from
baseline (p<0.001) compared to placebo. The patients who received sirukumab 100
12
mg every 2-weekly achieved the highest remission rates based on DAS-28 and
simplified disease activity index (SDAI) criteria throughout the study up to week 24.
The other novel IL-6 blocking agent which is currently under
development is olokizumab. It selectively blocks the final assembly of the IL-6
signaling complex (gp80 + gp130 + IL-6) [42]. A recent double-blind, placebo-
controlled pilot study, recruited 40 RA patients who were on a stable dose of
methotrexate but with a high CRP. They were randomised to a single dose of
olokizumab; either (0.1 or 1.0 mg/kg intravenously) or (1.0 or 3.0 mg/kg
subcutaneously), or a placebo. At 12 weeks, the results showed that regardless the
dose or route of administration, a single dose of olokizumab demonstrated prolonged
suppression of CRP. However, the CRP level in the 0.1 mg/kg intravenous group
showed some recovery after 28 days. Importantly, all doses were well tolerated. The
clinical efficacy and long-term tolerability of olokizumab will be explored further in
phase II trials that are currently recruiting patients.
Clinical Efficacy
The use of IL6-inhibitor has been tested in multiple large randomised
controlled trials. So far, only tocilizumab is licensed and will be the focus for
discussion below. 10 pivotal trials are elaborated here and summarised in Table 2.
Although the study protocols are different, majority of the studies used the same
clinical end-points; American College of Rheumatology (ACR) improvement
response, disease activity score in 28 joints (DAS-28), Health Assessment
Questionnaire of Disease Activity (HAQ-DI) from baseline and the Genant-Modified
Sharp score (GSS) in assessing the radiographic structural progression.
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4.1 Tocilizumab Monotherapy
The earliest Phase II double-blind placebo-controlled study was
conducted by Nishimoto and his colleagues in 2004. At that time, tocilizumab was
known as MRA. In this multi-centre study conducted in Japan, 164 patients with
refractory RA were randomised to receive either MRA (4 mg/kg body weight or 8
mg/kg body weight) or placebo [43]. MRA was given as monotherapy as all DMARDs
were withdrawn prior to the study. The primary end point was the ACR20 response
while secondary end points include the ACR50 & ACR70 responses, the DAS-28
responses and the safety profiles at 18 weeks. The results showed that at 3 months,
78% of patients in the 8 mg/kg group, 57% in the 4 mg/kg group and 11% in the
placebo group achieved at least a 20% improvement in disease activity according to
the ACR criteria (p < 0.001 for 8 mg/kg group versus placebo). The secondary end
points were all met with significant results versus the placebo particularly in the
8mg/kg monotherapy group. Most importantly, MRA was well tolerated; the incidence
of adverse events (mostly were mild) was 56%, 59%, and 51% in the placebo, 4
mg/kg and 8 mg/kg groups respectively and these were not dose dependent. An
increment in blood cholesterol was observed in 44.0% of the patients treated with
MRA although no cardiovascular complication was observed. These positive findings
in terms of clinical efficacy and tolerability have stimulated other phase III studies
examining the use of tocilizumab monotherapy.
The AMBITION (Actemra versus Methotrexate double-Blind
Investigative Trial In mONotherapy) study recruited 673 patients with different
selection criteria. 67% of the patients were methotrexate-naïve at baseline whereas
patients who had previously failed either methotrexate or a TNF-inhibitor were
excluded [44]. There were 3 arms in which patients were randomised to either an
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escalating dose of methotrexate or tocilizumab 8 mg/kg, with a separate sub-study (n
= 101) recruiting patients to placebo for 8 weeks followed by active treatment. The
primary endpoint was the ACR20 response at 24 weeks. The results showed non-
inferiority and in fact superiority of toclizumab versus methotrexate. The weighted
difference for ACR20 response at week 24 was 0.19 (95% CI 0.11 to 0.27, p<0.001).
Significant difference was evident as early as week 2. The superiority was also true
in the methotrexate-naïve patients in the sub-analysis. Other secondary end points
include the ACR50 & ACR70 responses, remission in the form of DAS-28<2.6,
achievement of moderate EULAR response and HAQ-DI from baseline also
demonstrated superiority of tocilizumab against methotrexate. Fungal infections were
more common in the methotrexate group. Four deaths occurred during the study,
three in the tocilizumab arm, of which one was thought remotely related to treatment
(gastrointestinal haemorrhage).
The SATORI study recruited 127 patients with an inadequate response
to methotrexate (MTX-IR) [45]. This double-blind Japanese study randomised
patients to either tocilizumab 8 mg/kg or to methotrexate 8 mg per week. The dose of
methotrexate is notably low in this study, in keeping with current practice then in
Japan. Nearly half of the participants from the control group (48%) withdrew from the
study mainly due to a poor response to the treatment. The primary outcome was
achieved in which with 80% tocilizumab-treated patients compared to 25% control
patients achieving the ACR20 response at week 24. Serum vascular endothelial
growth factor (VEGF) levels decreased significantly more in the tocilizumab group
than the control group. No significant difference was seen in the number of patients
discontinuing the study due to AEs. Nasopharyngitis was seen slightly more
frequently in the tocilizumab group.
15
The ACT-RAY is the only double-blind Phase III study that assessed
the efficacy and safety profile by either adding tocilizumab to methotrexate strategy
or switching methotrexate to tocilizumab monotherapy. This was done over a 2 year
period in patients who had an inadequate response to methotrexate (MTX-IR). The
results are now available at 52 weeks [46]. 556 patients were randomly assigned
either to continue methotrexate with the addition of tocilizumab 8 mg/kg 4-weekly or
switch to tocilizumab monotherapy. The primary endpoint was clinical remission rate
in the form of DAS-28 at week 52 while the secondary end points included other
symptomatic outcomes such as ACR responses, HAQ-DI and progression of
structural damage using GSS. The results showed that the DAS28–(ESR) remission
rate was significant in the add-on group compared to the switch to monotherapy
group, 45.5% and 36.6% respectively (p=0.03). Although all other secondary end
points showed improvements in both groups which was maintained throughout up to
week 52, there was no statistically significant superiority of the add-on strategy
against the switch to monotherapy strategy in all other composite measures. The
majority of the structural progression from baseline was arrested. However,
significantly more switch patient experienced radiographic progression than in the
add-on group. The rates of adverse events and serious infections were also
comparable. The only different but important safety issue was that treatment with
combination with methotrexate resulted in higher rate of deranged liver
transaminases (greater than 3 times of the upper normal limits) than the
monotherapy group, 11% and 3% respectively. This laboratory abnormality has been
a consistent finding from week 28 up to week 52.
The SAMURAI (Study of Active controlled Monotherapy Used for
Rheumatoid Arthritis, an IL-6 inhibitor) study was a Japanese open-label but x-ray
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reader-blinded study to examine primarily the effect of tocilizumab monotherapy on
radiographic progression based on van der Heijde-modified Sharp score (vdH-Sharp
score) at 52 weeks [47]. 306 patients were randomised to either 8mg/kg dose of
tocilizumab monotherapy group or DMARDs group (mostly combination DMARD
therapy including low-dose methotrexate). In terms of clinical efficacy, the secondary
end points showed superiority of tocilizumab monotherapy against the conventional
DMARDs therapy (p<0.001) for each of the ACR response component although this
was assessed unblinded. Clinical remission defined as DAS28<2.6 was achieved in
59% of patients receiving tocilizumab compared to only 3% of patients receiving
DMARDs (p<0.001).
In terms of long-term clinical efficacy, the STREAM (Long-term Safety
and efficacy of Tocilizumab, an anti-IL-6 REceptor monoclonal Antibody,
Monotherapy, in patients with rheumatoid arthritis) study is the longest study to-date,
with 5 years follow-up duration that assessed the safety and clinical efficacy [48].
This is an extension trial that was carried out by Nishimoto and his colleague
described earlier in this article [43] although the difference is that it is an open label
study after the initial double-blind trial. 66% of the 143 patients completed the 5
years study. Notably, the response rate according to the ACR improvement criteria
increased during the initial year and subsequently remained constant throughout the
study period. At 5 years, 84.0%, 69.1% and 43.6% of the tocilizumab group achieved
the ACR20, ACR50 and ACR70 responses respectively. In fact, improvement in all
other parameters including tender joint counts, swollen joint counts, CRP levels,
HAQ score and clinical remission (DAS28<2.6) from the earlier Phase II study was
sustained throughout the 5 year follow-up. Only one patient withdrew due to lack of
response while 22% withdrew due to adverse events.
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4.2 Tocilizumab with Combination Therapy (Methotrexate / DMARDs)
The earliest phase II study was CHARISMA (the Chugai Humanised
Anti-Human Recombinant Interleukin-6 Monoclonal Antibody). This was a
multicentre double-blind randomised controlled trial which recruited 359 European
patients who did not respond adequately to methotrexate (MTX-IR) [27]. The primary
clinical end-point was the ACR20 response at 16 weeks. The secondary end points
included the ACR50 and ACR 70 responses at 16 weeks, the DAS-28 response and
safety assessment up to the 20th week. The patients were assigned to either
receiving a placebo + methotrexate or tocilizumab at doses of 2 mg/kg, 4 mg/kg or 8
mg/kg, each with or without methotrexate. The results showed that at 16 weeks, the
ACR20 response was achieved by 61% and 63% in the 4 mg/kg and 8 mg/kg dose
of tocilizumab monotherapy groups respectively while 64% and 74% patients also
achieved this primary end point in those similar doses but with a combination with
methotrexate respectively. There were no significant differences in ACR20 response
rates between the placebo and 2 mg/kg dose groups. The only significant ACR50 &
ACR70 responses against the placebo + methotrexate group were seen in patients
on 8 mg/kg dose of tocilizumab plus methotrexate. Other secondary end point
showed that remission in the form of DAS-28 score was achieved by 34%, 17% and
8% in the 8 mg/kg dose of tocilizumab + methotrexate, 8 mg/kg dose of tocilizumab
monotherapy and placebo + methotrexate groups respectively. The study also
showed that responses to tocilizumab treatment were seen as early as week 4 and
were still improving at the study endpoint.
The OPTION (TOcilizumab Pivotal Trial in Methotrexate Inadequate
RespONders) study, a large double-blind placebo-controlled study, recruited 623
patients worldwide who had not responded to methotrexate adequately (MTX-IR)
18
[49]. All other DMARDs and Biologics were discontinued prior to the start of the
study. The primary end point was the ACR20 response at 24 weeks. The secondary
end points include ACR50 & ACR70 responses at 24 weeks, the DAS-28 response
and HAQ-DI to assess physical functionality. The patients were randomised to
tocilizumab 4 mg/kg, 8 mg/kg or placebo each with methotrexate at a stable dose.
The results showed that at 24 weeks, the ACR20 was achieved by 48% patients
allocated to tocilizumab 4 mg/kg, 59% patients receiving 8 mg/kg dose tocilizumab
and 26% patients in the placebo group (p < 0.0001). Significantly greater number of
patients receiving tocilizumab showed ACR50 and ACR70 responses and DAS-28
remission (DAS-28 < 2.6) at week 24 than those did in the placebo groups.
The ROSE (Rapid Onset and Systemic Efficacy) study was the first
Phase IIIb study which recruited 619 patients from various centres only in the United
States, who had an inadequate response to DMARDs (DMARDs-IR) [50]. Prior use
of other biologics was permitted and subsequently withdrawn before the
randomisation. Patients were randomised in a 2:1 basis to tocilizumab 8 mg/kg or
placebo while continuing a stable background DMARDs therapy. The primary
endpoint was the ACR50 response at week 24. The secondary end points include
the ACR20 & ACR70 responses, the DAS-28 response and the European League
Against Rheumatism (EULAR) response at 24 weeks. The results showed that the
ACR50 response at week 24 was significantly higher in the tocilizumab group than in
the placebo group (30.1% vs11.2%; p<0.0001). Significantly greater number of
patients receiving tocilizumab achieved the ACR20 and ACR70 responses and the
EULAR good response at all time points starting from week 4 and clinical remission
(DAS-28 < 2.6) at week 24 compared to the placebo group. A sub-study examining
early response to therapy was also undertaken and showed improved patient’s
19
global assessment of disease activity, pain, CRP and ESR in tocilizumab group
compared to placebo as early as day 7 but not in the swollen or tender joint counts
and physician’s global assessment.
Of all the Phase III studies, TOWARD (TOcilizumab With traditional
DMARD) recruited the largest patient population, 1,220 patients worldwide [51]. The
patients were randomised in a 2:1 manner to either tocilizumab 8 mg/kg or placebo
along with stable doses of DMARD therapy throughout. It is the only study which
exclusively excluded prior treatment with biologics. The primary endpoint was the
ACR20 response at 24 weeks. The results showed that in the tocilizumab group,
61% patients met the primary end point compared to 25% in the placebo group. The
improvement in the ACR response was consistent across the various types and
numbers of DMARDs used with the exception of patients receiving at least three
DMARDs in combination. All other secondary end points were also achieved notably
the ACR50 & ACR70 responses, which were apparent from Week 4 and continued
to Week 24. Adverse events (AEs) were reported more in the tocilizumab group
than the control group (73 vs. 61%) although withdrawals from study due to AEs
were infrequent. There was not a clear difference in serious infections. As the
participant numbers are large, this study adds the evidence of the efficacy and
relative safety of tocilizumab in combination with any other DMARDs available.
The RADIATE (Research on Actemra Determining EffIcacy after Anti-
TNF FailurEs) study is the only phase III multi-centre placebo-controlled trial which
recruited only patients who had previously failed TNF inhibitors (TNF-IR) [6]. 499
patients from North America and Europe were randomised to tocilizumab at a dose
of 8 mg/kg, 4 mg/kg or placebo along with a combination of methotrexate. Nearly half
the patients had failed one TNF inhibitor, 38% had failed two agents and 14% had
20
failed at least three. The primary end point was the ACR20 response at week 24
while the secondary end points include the ACR50 & ACR70 responses, the DAS-28
response and also the EULAR response. The results showed that both the 8 mg/kg
(50.0%) and 4 mg/kg (30.4%) groups exhibited superior ACR20 responses
compared with control (10.1%; p<0.001). Significant ACR50 & ACR70 responses,
EULAR responses were met in both groups receiving tocilizumab. However, the 8
mg/kg tocilizumab was more superior compared to the 4 mg/kg group notably in
terms of clinical DAS-28 remission. Interestingly, there was no definite relationship
between the ACR response rates and the number or type of prior TNF inhibitors.
The LITHE study was a double-blind randomised controlled trial with
the longest follow-up, 52 weeks [52]. 1,196 patients from 15 countries were recruited
and randomised to 3 arms; tocilizumab 8 mg/kg, 4 mg/kg or placebo, all in
combination with methotrexate. Prior TNF inhibitor therapy was allowed. A rescue
therapy of tocilizumab 4mg/kg was offered to the patients who did not receive 20%
improvement in terms of tender and swollen joint counts by week 16. The two
primary end points were the change from baseline in the radiographic score using
GSS and change in physical function using HAQ-DI at week 52. By the end of the
study period, half of the control group had received rescue treatment. Both primary
outcomes were met, with a 74% and 70% reduction in radiographic progression in
the tocilizumab 8 mg/kg and 4 mg/kg groups respectively. HAQ-DI improvement was
also significant in the treatment groups compared to the placebo groups. Other
efficacy analysis also showed that the ACR responses were greatest in the
tocilizumab 8 mg/kg group. No apparent differences were seen in exposure adjusted
rates of serious AEs between the tocilizumab and placebo groups.
21
4.3 Composite index without using acute phase reactants as measurement of
clinical efficacy
Most composite indexes such as ACR improvement criteria, DAS-28
and Simplified Disease Activity Index (SDAI) include either CRP or ESR in the
formula. Although it has been reported that the degree to which acute phase
reactants (APR) contribute to the constituent elements of the DAS28 is no more than
15% [53], there is always a theoretical assumption that these composite indexes
may overestimate the clinical response in patients treated with an IL-6 inhibitor
particularly in terms of the definition of remission [54]. This is particularly true as the
CRP production is induced mainly or not exclusively by the IL-6 cytokine although
the TNF and IL-1 cytokines have also indirect roles in the mediation [55, 56].
In order to tackle this, Clinical Disease Activity Index (CDAI), an index
that has been validated previously in assessing severity of RA was studied as it does
not include APRs [57, 58]. The formula for calculation is CDAI = TJC + SJC + GH +
EGA; where TJC = tender joint count (0–28), SJC = swollen joint count (0–28), GH =
patient’s assessment of general health (cm) and EGA = physician’s global
assessment (cm). The cut off points are: Remission (CDAI ≤2.8), Low Disease
Activity (CDAI between 2.8 and 10), Moderate Disease Activity (CDAI between 10
and 22) and High Disease Activity (CDAI > 22).
Kaneko and colleagues recruited 31 patients who were DMARD-IR or
TNF-IR, treated with tocilizumab 8mg/kg dose [59]. The length of follow-up was 52
weeks. The results showed that mean baseline of DAS28-ESR was 5.96, decreasing
to 2.89 at week 52 with a remission rate (DAS28-ESR<2.6) of 35.5%. On the other
hand, the mean baseline of CDAI was 28.4, falling to 10.2 at week 52 with a
22
remission rate (CDAI≤ 2.8) of 22.6%. Further analysis also showed that of patients
whose CRP levels were not detected by week 12, 65.2% achieved remission or low
disease activity as assessed by CDAI at week 52.
On a larger scale, Smolen and his colleagues obtained results from a
random sample of 80% patients from the 3 randomised clinical trials (LITHE,
OPTION & TOWARD) and pooled the results [60]. The patients were mainly
DMARD-IR and not methotrexate-naïve or TNF-IR. The results showed that in
patients treated with tocilizumab, the reduction in disease activity is statistically
significant against the placebo irrespective of the type of composite measures used
to evaluate disease activity. The remission rates in tocilizumab groups were much
higher using the DAS-28 compared to SDAI and CDAI, 30% against 7.7% & 6.4%
respectively. This can be explained by the high weight of the ESR in the DAS-28
calculation and the effect of tocilizumab on repressing the acute phase reactants.
Using the CDAI index, the remission rates in patients treated with tocilizumab were
in similar magnitude than those treated with tumour necrosis factor inhibitors.
4.4 Effect on Radiographic Progression
Osteoclasts are the key cells involved in mediating erosions in
inflammatory arthritis. Osteoclastogenesis occurs from the interaction between
receptor activator of NF-せB (RANK) and its ligand (RANKL) [61, 62]. In neonatal
mouse calvaria experiment, IL-6 in the presence of sIL-6R, enhanced the expression
of RANKL and osteoprotegerin (OPG) thus inducing bone resorption [19]. However
the RANK expression was also found decreased, suggesting that sIL-6R trans-
signalling influences osteoclastogenesis through osteoblast and osteoclast
interaction.
23
Applying this animal study finding to the human trials, both the LITHE
and ACT-RAY trials showed that tocilizumab retarded the structural disease
progression using Genant-modified Sharp score (GSS). In LITHE study, progression
of structural damage from baseline to week 52 was reduced by 74% and 70% with
tocilizumab 8mg/kg and 4 mg/kg both in combination with methotrexate, respectively,
as compared with controls (P<0.0001) [52]. The ACT-RAY study compared the effect
on radiographic progression between 2 groups; tocilizumab monotherapy and
tocilizumab + methotrexate. The radiographic progression was defined as any
change in GSS > the smallest detectable change (SDC) computed based on the
difference between the x-ray readers. The results showed that the overall
radiographic progression was small in both groups although it was statistically
significant (add-on therapy versus switch to monotherapy); 8% and 14% respectively
[46].
The SAMURAI study assessed the radiographic progression between
tocilizumab 8mg/kg monotherapy and DMARDS only groups based on a different
scoring system, van der Heijde-modified Sharp score (vdH-Sharp score) at 52
weeks. The results showed 56% of patients receiving tocilizumab had no
radiographic progression (i.e change from baseline in the total Sharp Score (TSS)
≤0.5 compared with 39% of patients receiving conventional DMARDs (p<0.01) [47].
In addition, the erosion scores and joint space narrowing scores also showed
significantly less change in the tocilizumab group than in the DMARD group.
Recently, studies exploring the structural progression using magnetic
resonance imaging (MRI) are under way. Results from 12 weeks study showed that
treatment with tocilizumab is associated with early suppression of synovitis and
24
osteitis, with no mean increase in the erosion score [63]. There was no statistically
different between tocilizumab monotherapy and in combination with methotrexate.
4.5 Other Clinical Efficacy
Treatment with tocilizumab also increases the haemoglobin level in
various phase III studies whether it is administered as a monotherapy or in
combination with other conventional DMARDs. In STREAM study, most patients
exhibited anaemia at baseline and the mean haemoglobin level was 11.3 ± 1.4 mg/dl
(SD 1.4) [48]. After 5 years follow-up, treatment with tocilizumab significantly
improved anaemia in these patients and the mean haemoglobin level increased to
13.2 ± 1.5 mg/dl (SD 1.5). The AMBITION study also indicated that the improvement
in haemoglobin levels was seen as early as week 2 with normalisation of mean
haemoglobin by week 6 and subsequently maintained through to week 24 [44].
The HAQ-DI is designed to assess the patient’s usual abilities and
physical function. It is composed of 20 items from 8 different categories. The HAQ-DI
is sensitive to change and is a good predictor of future disability and costs [64, 65].
Again, various tocilizumab trials showed improvement of HAQ-DI from baseline. In
LITHE study, at 52 weeks, ANOVA of the adjusted mean area under curve (AUC) of
the change in the HAQ-DI score from baseline showed a significantly greater
decrease in the tocilizumab 8-mg/kg and 4-mg/kg plus MTX groups (–144.1 and -
128.4 units, respectively) than in the control group taking placebo plus MTX (–58.1
units; P <0.0001 for both comparisons) [52].
25
5. Safety Profile
In an analysis of cumulative safety data from five pivotal phase III trials
and two extension trials, two populations were studied. The first group is the patients
randomised to the different treatment arms during the controlled portions of the
studies, followed until the first change in treatment regimen or until 2 years of
treatment (n = 4,199, controlled population). The second group comprised those who
were exposed to at least one dose of tocilizumab (n = 4,009, all-exposed population)
[66]. The analysis which consisted of mean treatment duration of 2.4 years,
confirmed that the long-term safety profile of tocilizumab was comparable with that
observed in the phase 3 studies (duration up to 1 year).
The overall rate of adverse events (AEs) was 339.0/100 patient years
(PY) in the control group, 358.0/100 PY in the tocilizumab 4-mg/kg group and
381.6/100 PY in the tocilizumab 8-mg/kg group in the all-controlled population group.
In the all-exposed groups, the rate of AEs was 278.2/100 PY in which elevated
transaminases levels and infections were the commonest AEs reported. The rate of
serious adverse events (SAEs) was not different between the groups and did not
increase with prolonged exposure. In fact, the rates of SAEs, including deaths, were
similar to those observed in other biologics clinical trials in RA although direct
comparison as always may not be accurate as different study protocol and designs
were employed.
5.1 Infections
In the all exposed population, the rates of serious infections were the
highest in the tocilizumab 8-mg/kg group compared to the tocilizumab 4-mg/kg group
and the control group; 4.9/100 PY, 3.5/100 PY and 3.5/100 PY respectively.
26
Regardless of the different exposed groups, serious infection cases were attributed
to other confounding factors such as patient’s pre-existing pulmonary disease,
diabetes, older age, high body mass index, concomitant steroids or prior treatment
with a TNF inhibitor [66]. Skin and respiratory tract infections were commonly
reported. Seven cases of tuberculosis were reported in the all-exposed group
although it was uncertain whether these were new cases or cases in which the initial
screening for latent tuberculosis was inadequate. One report of leucoencephalopathy
[67] was associated with tocilizumab while one fatal case of reactivation of HBV was
reported by Nishimoto [43]. Notably, similar to serious adverse events, the rate of
serious infections was stable over time.
In another meta-analysis of 6 randomised controlled trials, 4 of which
were again included in the analysis (RADIATE, OPTION, TOWARD and AMBITION),
after excluding CHARISMA study due to small number of subjects, the authors found
that combination treatment with tocilizumab 8mg/kg and methotrexate resulted in
greater risk of serious infection when compared with controls (OR = 1.78; 95% CI
0.98, 3.23) [68]. This however is a lesser risk compared to TNF-inhibitor as a meta-
analysis of harmful effects in RCTs involving anti-TNF inhibitor therapy concluded
that the pooled OR for serious infection in comparison with controls was 2.0 (95% CI
1.3, 3.1) [69]. Direct comparison should be carefully interpreted though. The
TOWARD trial reported opportunistic infection as one patient was diagnosed with
Mycobacterium avium intracellulare after found to have an abnormality on a chest x-
ray [51]. The main safety profiles are summarised in Table 3.
27
5.2 Laboratory Abnormalities
Elevated levels of hepatic transaminases (ALT and AST) were
observed in about one third of the tocilizumab-treated patients. The increment was
generally mild and reversible. Increment in ALT particularly more than 3 x upper limit
of normal value (ULN) in patients treated with tocilizumab were less common with
tocilizumab monotherapy [66]. Importantly, no association between liver enzyme
elevation and clinically apparent drug-induced liver injury was demonstrated. Of the
11 liver biopsy samples that were done, only 9 steatohepatitis cases were present in
which the patients also have other risk factors such as obesity and diabetes [44, 66].
Neutropenia largely due to migration of neutrophils [70] was commonly
reported in patients treated with tocilizumab. Generally, this was not associated with
an increased risk of infections. In the all-exposed population, 32 patients had
thrombocytopenia with either a Grade 3 or Grade 4 in which one reported to have a
serious bleeding event (haemorrhagic stomatitis) [66]. The infusion was maintained
and the event subsequently resolved without further complication. Temporary
thrombocytopenia resulted from the decrease in IL-6 after starting tocilizumab as
thrombocytosis is mediated by IL-6 [28].
Alteration in lipid profiles was also linked to treatment with tocilizumab.
A possible explanation is that active RA is associated with lowering of the serum
cholesterol and LDL levels thus treatment with tocilizumab returns these levels to
what would be ‘normal’ for that patients [71-73]. On a positive note, the STREAM
study found no evidence of an increased risk of cardiovascular disease at 5-year
follow-up [48]. Furthermore, the rates of myocardial infarctions and strokes were
28
similar in the tocilizumab treatment groups as in the control group and did not
increase over time. The main laboratory abnormalities are summarized in Table 4.
5.3 Malignancy
The overall rate of solid malignancy in the all-exposed group was
1.1/100 PY and was stable even after prolonged exposure [66]. This is comparable
to other biologic treatments. For instance, in a large contemporary United States
cohort of RA patients, the rate of malignancy was 1.3/100 PY of which 62% were
treated with TNF inhibitors [74]. Interestingly, in animal studies, IL-6 appears to have
tumour promoting activity and targeting IL-6 pathways may be effective in some
cancers [75, 76]. However, this needs to be translated into human observational
studies.
5.4 Other Safety Profile
Clinically significant hypersensitivity reactions were reported in about
1% of patients and occurred mainly within the first four infusions [66]. Anaphylactic
reaction was more common in the toclizumab 4mg/kg group than the 8mg/kg group
[28]. Antibodies to tocilizumab occurred in about 2-4% of the patients although this
did not seem to predispose the hypersensitivity reactions [28].
The rate of gastrointestinal perforations was 0.28/100 PY in the all-
exposed group [66]. The majority of these patients had a history of diverticulitis and
concurrent use of NSAIDs or steroid which put them at further risk.
Recent evidence has suggested that TNF inhibitors are associated with
the development of demyelinating disease [77, 78] . It is still uncertain whether this is
also the case with tocilizumab treatment. Until data are widely available, caution
29
needs to be taken in prescribing tocilizumab particularly in patients with pre-existing
disease and in patients with a positive family history of demyelinating disease [28].
6. Expert Opinion
The value of blocking IL-6 lies in its versatility in neutralising various
cytokine pathways responsible for immune regulation, haematopoiesis and
inflammation. IL-6 is a potent pro-inflammatory agent that induces fever, fatigue and
many other clinical attributes associated with inflammation. Thus blocking IL-6
pathway has proven popular in recent times in treating systemic inflammatory
disease like RA and systemic JIA.
In terms of RA, anti-IL-6 receptor monoclonal antibody, tocilizumab, is
licensed for use in patients with moderate to severe active disease, who has shown
inadequate response to at least one sDMARD including methotrexate or after failure
to an anti-TNF. In terms of selection choice, the patients that would gain most are
the ones with high inflammatory markers and who are symptomatic with fatigue
secondary to anaemia.
The success of treatment with tocilizumab is evidenced by ample
phase II and III randomised controlled trials and open-label extension studies.
Primary end points were achieved comparable to other biologics like TNF inhibitors,
abatacept and rituximab. Importantly, deterioration in structural progression was also
halted. Combination therapy with methotrexate at least at the start of the treatment,
is still the preferred choice of administration to the patients due to better numerical
values in the study results in terms of clinical efficacy. Combination with other
sDMARDs such as hydroxychloroquine, sulfasalazine and leflunomide was also
effective without notable differences [51, 79]. Combination therapy however is
30
associated with an increased risk of elevated transaminases. Hence studies
concerning at which point methotrexate can be tapered down or remission-type
studies at which point the treatment dose of tocilizumab can be spread out are of
interest.
The ACT-RAY trial showed that switching to monotherapy was non-
inferior to combination therapy with methotrexate despite achieving meaningful
clinical efficacy and halted structural progression. This is particularly of benefit in
patient who has intolerance or experiences side effects from methotrexate. The
recommended dose as monotherapy is 8mg/kg given every 4 weeks. Various
national registries have revealed that about one third of the patients worldwide are
on biologic monotherapy [80, 81]. Perhaps this is the strongest selling point of
tocilizumab as to date, it is one of the few biologics given as a monotherapy that
have shown superiority against methotrexate in head-to-head studies [44]. In fact the
ADACTA trial recently revealed clinical superiority of tocilizumab therapy against
adalimumab monotherapy although comparison was not done against combination
treatment of adalimumab + methotrexate [82].
In terms of feasibility, patient’s preference remains the priority. As it is
administered intravenously every 4 weeks, it suits patients adverse to subcutaneous
injections of biologic treatment or those who are able to travel to hospital. An
advantage of IV administration is that blood tests particularly fasting lipid profiles at
intervals can be monitored more carefully. On the other hand, this also increases the
cost of treatment further in terms of staffing resources. Hence, the development of
subcutaneous tocilizumab and other IL-6 agents that are currently in the Phase III
trials are eagerly anticipated.
31
Tolerability and safety data will always be the top priority in a novel
treatment of a chronic condition. Although tocilizumab does not have the long-term
safety record of the TNF inhibitors, which have been licensed for 13 years, the
overall safety data appears comparable [71]. A meta-analysis of the risk of adverse
events has revealed a small but significant increase in AEs and infections in patients
treated with 8 mg/kg of tocilizumab compared with controls. Hence, vigilance is
needed particularly when treatment is offered to patients with multiple comorbidities
and the elderly population. The rate of SAEs and death were comparable to other
biologics that are currently available. It is still uncertain whether treatment with
tocilizumab can lead to re-activation of tuberculosis and induces demyelinating
disease. Until then, the patients should be screened for these 2 conditions as per
other biologics prior to starting treatment.
Long-term cardiovascular safety is of major concern in systemic
inflammatory disease and patients with rheumatoid arthritis are more likely to have
macrovascular complications compared to the general population [83, 84].
Elevations in liver function tests which followed the ‘saw-tooth’ pattern between the
infusions were frequent in patients receiving tocilizumab in a dose-dependent
manner, particularly in combination with methotrexate. So far, data from a 5-year
study has shown that the elevated lipid profiles were not associated with an
increased risk of major cardiovascular events [48].
7. Conclusion
Data from clinical trials and meta-analysis have shown that both clinical
efficacy (even when using a composite index that exclude acute phase reactant in
the formula like CDAI) and safety profile of IL-6 blocking agents, notably tocilizumab,
32
are comparable to that of other biologics that are available for use in RA. More
longer term studies exploring the macrovascular complications, assessment of
structural progression using modality like ultrasound and MRI together with the
development of IL-6 agents administered using subcutaneous form over the next few
years, should make targeting IL-6, a mainstay in the treatment of RA.
Conflicts of Interest
Md Yuzaiful Md Yusof – no conflicts of interest
Paul Emery – Consulting fees for Pfizer, Merck, Abbott, BMS, UCB
No funding involved
33
Table 1: Interleukin-6 blocking agents other than intravenous tocilizumab currently under development
Drugs Tocilizumab [26] Sarilumab [39] BMS945429 [40] Sirukumab [41] Olokizumab [42]
Pharmacology
description
IL-6 receptor
monoclonal
antibody that binds
to both soluble &
membrane-bound
receptor
IL-6 receptor
monoclonal
antibody that binds
to the alpha subunit
of the IL-6 receptor
complex
An aglycosylated,
humanised, anti–IL-
6 monoclonal
antibody that binds
directly to IL-6
Humanised
monoclonal
antibody against
soluble IL-6
receptor
Selectively blocks
the final assembly
of the IL-6 signaling
complex (gp80 +
gp130 + IL-6)
Method of
administration
Subcutaneous Subcutaneous Intravenous Subcutaneous Subcutaneous /
Intravenous
Study phase
completion
Phase III Phase II Phase II Phase II (Proof of
concept)
Pilot Studies
Trials Duration 2 years (results at
Week 24)
12 weeks 12 weeks 24 weeks 12 weeks
34
Dosing /
Comparator
S/c TCZ 162mg +
DMARDs vs IV TCZ
8mg/kg + DMARDs
S/c SRL 100mg
q2W vs SRL 150mg
q2W vs SRL 100mg
qW vs SRL 200mg
q2W vs SRL 150mg
qW vs Placebo*
S/c BMS 80mg vs
BMS 160mg vs
BMS 320mg vs
Placebo*
Placebo + S/c SRK
100mg q2W vs
SRK 100mg q2W
vs SRK q4W vs
SRK 50mg q4W vs
SRK 25mg q4W*
Single dose either
IV (0.1 or 1mg/kg)
or S/c (1 or 3mg/kg)
vs placebo
Number of patient 1262 306 127 151 40
ACR 20 69/73 49/66/52/65/72/46 81/71/82/27 N/A N/A
ACR 50 N/A 22/35/40/40/30/15 34/27/50/9 37/60/50/30/36 N/A
ACR 70 N/A 6/12/16/17/16/2 13/12/25/3 N/A N/A
* Each treatment arm is in combination with methotrexate; ACR20, 50 & 70: American College of Rheumatology responses (20%,
50% and 70% improvement from baseline in terms of both tender and swollen joint counts along with 3 out of the 5 other core data
set measures), BMS: BMS945429, DMARDs: Disease Modifying Anti-Rheumatic Drugs, IL-6: Interleukin 6, IV: Intravenous, qW:
every week, q2W: every 2-week, q4W: every 4-week, S/c: subcutaneous, SRL: Sarilumab, SRK: Sirukumab
35
Table 2: Percentage of patients who met the American College of Rheumatology (ACR) 20, 50 and 70 improvement criteria based
on the randomised controlled trials of tocilizumab monotherapy and in combination treatment with methotrexate / DMARDs.
Follow
Up
(Weeks)
Study
Number
of
patients
Criteria
Dosing Schedule
% who met
ACR20
according to
dose
% who met
ACR50
according to
dose
% who met
ACR70
according to
dose
Tocilizumab Monotherapy
12 Nishimoto [43] 164 DMARD-IR Placebo vs TCZ 4mg/kg
vs TCZ 8mg/kg
11/ 57/ 78 2/ 26/ 40 0/ 20/ 16
16 CHARISMA [27] 359 MTX-IR MTX vs TCZ 2mg/kg vs
TCZ 4mg/kg vs TCZ
8mg/kg
41/ 31/ 61/ 63 29/ 6/ 28/ 41 16/ 2/ 6/ 16
24 AMBITION [44] 673 MTX-Naïve
(67%)
MTX vs TCZ 8mg/kg 53/ 70 34/ 44 15/ 28
24 SATORI [45] 127 MTX-IR MTX vs TCZ 8mg/kg 25/ 80 11/ 49 6/ 30
52 ACT-RAY [46] 556 MTX-IR MTX + TCZ 8mg/kg vs
TCZ + Placebo
71/ 69 50/ 55 31/ 31
52 SAMURAI [47] 306 DMARD-IR DMARDs vs TCZ 8mg/kg 34/ 78 13/ 64 6/ 44
36
ACR20: American College of Rheumatology 20 response (20% improvement from baseline in terms of both tender and swollen
joint counts along with 3 out of the 5 other core data set measures), DMARD-IR: Inadequate Response to Disease Modifying Anti-
Rheumatic Drugs, MTX-IR: Inadequate Response to Methotrexate, N/A: Data not available, TCZ: Tocilizumab.
Combination Therapy (Tocilizumab + Methotrexate / Other DMARDs)
16 CHARISMA [27] 359 MTX-IR MTX vs TCZ 2mg/kg vs
TCZ 4mg/kg vs TCZ
8mg/kg
41/ 64/ 63/ 74 29/ 32/ 37/ 53 16/ 14/ 12/
37
24 OPTION [49] 623 MTX-IR Placebo vs TCZ 4mg/kg
vs TCZ 8mg/kg
26/ 48/ 59 11/ 31/ 44 2/ 12/ 22
24 ROSE [50] 619 DMARD-IR Placebo vs TCZ 8mg/kg N/A 11/ 30 N/A
24 TOWARD [51] 1220 MTX /
DMARD-IR
Placebo vs TCZ 8mg/kg 25/ 61 9/ 38 3/ 21
24 RADIATE [6] 499 TNF-IR Placebo vs TCZ 4mg/kg
vs TCZ 8mg/kg
10/ 30/ 50 4/ 17/ 29 1/ 5/ 12
52 LITHE [52] 1196 MTX-IR Placebo vs TCZ 4mg/kg
vs TCZ 8mg/kg
25/ 47/ 56 10/ 29/ 36 4/ 16/ 20
37
Table 3: The main safety profiles of tocilizumab as reported in phase III randomised controlled trials. Figures are in numbers (%).
Study Number of
patient
Dosing
Schedule
Withdrawals
due to AEs
Number of
AEs
Number of
SAEs
Serious
Infection
Deaths Malignancy
Tocilizumab Monotherapy
ACT-RAY
[46]
556 TCZ 8mg/kg
+ MTX
TCZ 8mg/kg
+ Placebo
21 (7.6)
17 (6.2)
227 (81.9)
228 (82.6)
24 (8.7)
26 (9.4)
10 (3.6)
9 (3.3)
2 (0.7)*
2 (0.7)*
N/A
N/A
AMBITION
[44]
673 TCZ 8mg/kg
MTX
11 (3.8)
15 (5.3)
230 (79.9)
220 (77.5)
11 (3.8)
8 (2.8)
4 (1.4)
2 (0.7)
3 (1.0)*
1 (0.4)
1 (0.3)
3 (0.1)
Combination Therapy (Tocilizumab + Methotrexate / DMARDs)
LITHE [52] 1196 TCZ 4mg/kg
TCZ 8mg/kg
Placebo
28 (7)
33 (8)
11 (3)
324**
325.4**
279.6**
12.8**
11.5**
10.2**
3.7**
4.0**
2.3**
0 (0)
4 (1)*
2 (0.5)
5 (1.3)***
2 (0.5)***
1 (0.3)***
38
OPTION [49] 623 TCZ 4mg/kg
TCZ 8mg/kg
Placebo
14 (6.5)
12 (5.9)
6 (2.9)
151 (71)
143 (69)
129 (63)*
13 (6)
13 (6)
12 (6)
3 (1)
6 (3)
2 (1)
N/A
N/A
N/A
0
0
2 (1)
RADIATE [6] 499 TCZ 4mg/kg
TCZ 8mg/kg
Placebo
10 (6.1)
10 (6.1)
8 (5.0)
147 (84.0)
142 (87.1)
129 (80.6)
12 (7.4)
11 (6.3)
18 (11.3)
3 (1.8)
8 (4.6)
5 (3.1)
0
0
0
N/A
N/A
N/A
ROSE [50] 619 TCZ 8mg/kg
Placebo
27 (6.6)
8 (3.9)
290 (70.9)
122 (59.5)
30 (7.3)
11 (5.4)
12 (2.9)
1 (0.5)
3 (0.7)*
0
4 (1.0)
3 (1.5)
TOWARD
[51]
1220 TCZ 8mg/kg
Placebo
31 (3.9)
8 (1.9)
584 (72.8)
253 (61.1)
54 (6.7)
18 (4.3)
22 (2.7)
8 (1.9)
2 (0.2)*
2 (0.5)
N/A
N/A
* Of the 16 total of deaths, 6 were considered probably related to drug treatment (1 from AMBITION: gastrointestinal haemorrhage,
1 from ACT-RAY: Sepsis, 2 from LITHE: pulmonary embolism and gastrointestinal infection & 2 from ROSE: Sepsis and
haemorrhagic stroke), the author did not disclose the relation of treatment to death in TOWARD, the death cases for ACT-RAY was
from the preliminary 24 weeks data; ** Data reported per 100 patient-years, *** Data for solid malignancies only, AEs: Adverse
events; SAEs: Serious adverse events, MTX: Methotrexate, N/A: Not available, TCZ: Tocilizumab.
39
Table 4: Laboratory abnormalities secondary to tocilizumab treatment as reported in Phase III randomised controlled trials. Figures
are in numbers (%)
Study Number of
patient
Dosing
Schedule
Raised ALT
> 3 x ULN
Raised
Bilirubin
> 3 x ULN
Neutropenia
Grade 3
Neutropenia
Grade 4
Raised Total
Cholesterol
≥ 240mg/dL
Raised LDL
Cholesterol
≥ 160 mg/dL
Tocilizumab Monotherapy
ACT-RAY
[46]
556 TCZ 8mg/kg
+ MTX
MTX +
Placebo
3 (7)
1 (2)
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
AMBITION
[44]
673 TCZ 8mg/kg
MTX
(1.7)
(3.6)
(7.6)
(0.7)
(3.1)
(0.4)
0
0
(13.2)
(0.4)
(3.1)
(0)
Combination Therapy (Tocilizumab + Methotrexate / DMARDs)
LITHE [52] 1196 TCZ 4mg/kg
TCZ 8mg/kg
28 (7)
36 (9)
24 (6)
40 (10)
7 (1.8)
17 (4.3)
2 (0.5)
1 (0.3)
56 (14)
102 (26)
53 (14)
70 (18)
40
Placebo 3 (0.8) 5 (1.3) 0 (0) 0 (0) 31 (8) 15 (3.8)
OPTION [49] 623 TCZ 4mg/kg
TCZ 8mg/kg
Placebo
15 (7)
28 (14)
9 (4)
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
55 (26)*
43 (21)*
7 (3)*
N/A
N/A
N/A
RADIATE [6] 499 TCZ 4mg/kg
TCZ 8mg/kg
Placebo
4 (2.5)
4 (2.2)
1 (0.6)
N/A
N/A
N/A
1 (0.6)
4 (2.2)
0 (0)
1 (0.6)
4 (2.2)
0 (0)
N/A
N/A
N/A
25 (15.3)
21 (12)
6 (3.8)
ROSE [50] 619 TCZ 8mg/kg
Placebo
12 (3.1)
2 (1.2)
N/A
N/A
12 (2.9)
0 (0)
0
0
78 (21.9)
13 (7.7)
97 (32.3)
12 (9.2)
TOWARD
[51]
1220 TCZ 8mg/kg
Placebo
(4.1)
(0.7)
(8.9)
(0.7)
(3.7)
(0)
0
0
(23)
(5.5)
(16.1)
(3.4)
* The author used 6.2 mmol/l as the cut-off points which are equivalent to 250 mg/dL; ALT: Alanine aminotransferase,
DMARDs: Disease Modifying Anti-Rheumatic Drugs, LDL: Low density lipoprotein, MTX: Methotrexate, N/A: Not available,
ULN: Upper limit of the normal value.
41
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46
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